Rearrangement of NOTCH1 or BCL3 can independently trigger progression of CLL

Keersmaecker, Kim De; Michaux, Lucienne; Bosly, André; Graux, Carlos; Ferreiro, Julio Finalet; Vandenberghe, Peter; Cools, Jan; Włodarska, Iwona

doi:10.1182/blood-2011-10-388124

Cited by 10 publications

(6 citation statements)

References 10 publications

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“…The disappearance of NOTCH1 mutation after treatment has been previously reported in one patient. 21 The use of the more sensitive clonospecific PCR demonstrated low levels of cells with NOTCH1 mutation in the three cases. The identification of these small subclones carrying the mutation may reflect the complex fluctuation of different tumor subclones in the evolution of the disease.…”

Section: Discussionmentioning

confidence: 88%

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome

et al. 2012

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NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.

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Section: Discussionmentioning

confidence: 88%

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome

et al. 2012

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“…Intriguingly, the translocation was detected at the time of Richter transformation of a trisomy 12‐positive CLL, suggesting its essential role in disease progression. This finding places the PDL2 gene together with MYC , BCL3 , BMI1 , and NOTCH1 on a list of genes implicated in high grade transformation of CLL (Martin‐Subero et al, ; De Keersmaecker et al, ; Put et al, ; Rouhigharabaei et al, ). Mechanisms of deregulation of the PDL locus by non‐ IG partner sequences have not been completely deciphered.…”

Section: Discussionmentioning

confidence: 92%

Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies

Roosbroeck

Ferreiro

Tousseyn

et al. 2016

Genes Chromosomes & Cancer

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The recurrent 9p24.1 aberrations in lymphoid malignancies potentially involving four cancer-related and druggable genes (JAK2, CD274/PDL1, PDCD1LG2/PDL2, and KDM4C/JMJD2Cl) are incompletely characterized. To gain more insight into the anatomy of these abnormalities, at first we studied 9p24.1 alterations in 18 leukemia/lymphoma cases using cytogenetic and molecular techniques. The aberrations comprised structural (nine cases) and numerical (nine cases) alterations. The former lesions were heterogeneous but shared a common breakpoint region of 200 kb downstream of JAK2. The rearrangements predominantly targeted the PDL locus. We have identified five potential partner genes of PDL1/2: PHACTR4 (1p34), N4BP2 (4p14), EEF1A1 (6q13), JAK2 (9p24.1), and IGL (22q11). Interestingly, the cryptic JAK2-PDL1 rearrangement was generated by a microdeletion spanning the 3'JAK2-5'PDL1 region. JAK2 was additionally involved in a cytogenetically cryptic IGH-mediated t(9;14)(p24.1;q32) found in two patients. This rare but likely underestimated rearrangement highlights the essential role of JAK2 in B-cell neoplasms. Cases with amplification of 9p24.1 were diagnosed as primary mediastinal B-cell lymphoma (five cases) and T-cell lymphoma (four cases). The smallest amplified 9p24.1 region was restricted to the JAK2-PDL1/2-RANBP6 interval. In the next step, we screened 200 cases of classical Hodgkin lymphoma by interphase FISH and identified PDL1/2 rearrangement (CIITA- and IGH-negative) in four cases (2%), what is a novel finding. Forty (25%) cases revealed high level amplification of 9p24.1, including four cases with a selective amplification of PDL1/2. Altogether, the majority of 9p24.1 rearrangements occurring in lymphoid malignancies seem to target the programmed death-1 ligands, what potentiates the therapeutic activity of PD-1 blockade in these tumors. © 2016 Wiley Periodicals, Inc.

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“…An additional 10% to 20% of T-ALL patients contain mutations in FBW7, 2 the E3 ubiquitin ligase responsible for the degradation of NOTCH1, C-MYC, Cyclin E, and C-FOS. [3][4][5][6] NOTCH1 activation may contribute to the development of other hematopoietic malignancies, including chronic lymphocytic leukemia [7][8][9] and mantle cell lymphoma. 10,11 These findings support the continued development of NOTCH inhibitors as cancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells

Roderick

Tesell

Shultz

et al. 2014

Blood

130

118

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Rearrangement of NOTCH1 or BCL3 can independently trigger progression of CLL

Cited by 10 publications

References 10 publications

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome

Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies

c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells

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